Significance: COVID-19 causes significant lung damage in a subset of patients leading to a cascade of inflammatory cytokine activation (cytokine storm) that develops into acute respiratory distress syndrome (ARDS). There are several classes of FDA-approved therapeutics that have significant potential in mitigating the pulmonary inflammation when effectively delivered into the lower airways. However, there is a significant technology gap in the ability to safely and rapidly dose and administer these drugs to the lungs. Nebulizers are not used for Covid19 patients due to sterility/transmission risks since their use enables viral particles to linger in the air for hours; they are also not easy to use or sterilize. Inhalers produce mists that do not reach the lower airways. We have developed a patented platform trans-tissue delivery system (Droplette) comprising the unique combination of a piezoelectric transducer and diaphragm pump to physically deliver large therapeutics into cells and deep through tissue. We hypothesize that this device will allow deep and more rapid delivery into the lower airways into the lungs of COVID-19 patients relative to standard nebulizers without requiring active inhalation based on the measured droplet sizes (<3 m) in the mist generated by the device (i.e this can function as a rapid, low cost, more effective nebulizer for at-home use). Early intervention and at- home administration will reduce the hospitalization burden and need for ventilation- leading to decreased hospitalization rates, fewer patients who need to be placed on a ventilator and lower mortality. Additionally, the device accepts pre-filled sterile one-time use cartridges containing therapeutic formulations and is Bluetooth- enabled with a paired app, allowing a provider to monitor patients? usage via telemedicine. Preliminary Data: Droplette has been tested extensively across ex vivo, in vivo, and pilot human studies. We have previously demonstrated that Droplette can deliver naked large (>1 MDa) mRNA to the basal layer of mucosal tissue and hypothesize that the same mechanism can enable pulmonary delivery. The device generates a fine, low- pressure mist in a unique transitional flow regime and produces consistent spray pattern, plume geometry, droplet size distribution, and particle size. Droplette generates 100% fine mist (<4.7 m) that dispenses ~1mL/min with a flow velocity of 1-5 m/s. Specific Aims: We will demonstrate that Droplette can deliver therapeutics into the lungs & lower airways. In Specific Aim 1 we will Assess efficacy and delivery of Droplette paired with Hypertonic Saline (7%) (HS-7%) in treating ARDS/Cytokine storm using cascade impaction studies and cell/animal studies using models that will mimic a COVID-19 like cytokine storm. In Specific Aim 2, we will do the same set of studies using two classes of therapeutics currently in trials for COVID-19: epinephrine & anti- IL-6 antibodies. Collectively, the results from these studies will demonstrate efficacy of our device for pulmonary delivery in COVID-19 patients to treat cytokine storms & resulting lung damage.